Understanding the homeostatic response to PARP inhibitors in breast cancer
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Embargo End Date
2027-05-13
ICR Authors
Authors
Wicks, A
Document Type
Thesis or Dissertation
Date
2025-05-13
Date Accepted
Abstract
PARPi show significant antitumor activity in BRCA1/2 mutant tumours, but many patients develop
resistance, and the underlying causes are often unknown. Predominantly our understanding of
resistance to PARPi has originated from studies utilising genetic approaches, and relatively little is
understood about the protein expression changes induced by PARPi, and how these changes could
give rise to PARPi resistance. In this thesis, I used mass spectrometry based proteomic profiling of
both tumour cell lines and patient derived tumour organoids to define the proteomic response to
PARPi exposure. I integrated the information gained from this proteomic profiling with genetic
perturbation screens, particularly CRISPR activation screens, to identify candidate gain of function
mechanisms of PARPi resistance. I identified upregulation of the cohesin loader NIPBL as a
candidate driver of PARP inhibitor resistance. Examination of tumour RNA-seq data from advanced
breast cancer patients with PARPi resistance indicated that NIPBL might be upregulated in the PARPi
resistant state. By conducting functional studies in in vitro models, I confirmed that upregulation of
NIPBL confers PARPi resistance, and likely does so by restoring the localisation of RAD51 to the site
of DNA damage in BRCA1/2 mutant cells that otherwise have a RAD51 defect. Together, the data
presented in this thesis offers a foundation for understanding the homeostatic responses to PARPi
exposure which could drive PARPi resistance in BRCA1/2 mutant tumours.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Gene Function